Alteration in Toll-like Receptors Activation During Trichinella spiralis Infection

Trichinellaspiralis[T. spiralis]is a widespread zoonotic helminth. It can be considered as the most successful parasite in its two intracellular habitats; the intestine andskeletal muscles. All the stages in the life cycle ofT. spiraliscan occur in a single host; the adult, newborn larvae and encysted muscle larvae [1].

The chronic nature ofT. spiralisinfection in the muscles indicates that this parasite could subvert the host immune system through different mechanisms including induction of regulatory T and B cells and alternatively activatedmacrophagesand production of anti-inflammatorycytokinese.g. interleukin [IL]- 10 and transforming growth factor [TGF]- β [2]. One more important mechanism is by interfering with both the expression and function of toll- like receptors [TLRs] [3].

T. spiraliscan modulate the immune system producing T helper [Th]1/Th2 immune response with predominant cell type Th2 response with induction of T-regulatory [Treg] cells. This immunomodulation is beneficial for both the human host and the parasite; it could protecthelminthesfrom being eradicated and, at the same time, protect the host from excessive pro-inflammatory responses that may lead to organ damage [4].

In the past few years, new insights have been gained about the role of TLRs in health and disease. TLRs are expressed by many immune and non-immune cells such asdendritic cells, macrophages,neutrophils,lymphocytesandendothelialcells. This differential pattern of expression is one mechanism to ensure a more diverse response to different types of pathogens [3]. TLRs play essential roles in innate immune responses by recognizing various pathogen-derived components. TLRs signaling pathways triggered various转录factors e.g. nuclear factor [NF]-κB and activating protein [AP]-1, which are responsible for inflammatory responses [5].

TLRs play an important role in the immune responses against helminth infections, because excretory- secretory [ES] proteins andglycoproteins从驱虫的寄生虫已经证明了to activate immune cells via an immune re¬sponse related to TLRs [6,7].T. spiralisin particular releases abundant glycoproteins throughout its life which act as TLR ligand [8]. Different stages ofT. spiralishad different impacts on the expression of TLRs and related signaling molecules that may influence cytokine response of host [9]. However, few studies report the variation of TLR gene expression and their related signal pathway duringT. spiralisinfection.

Myeloid differentiation factor 88 [MyD88] is a signaling adaptor molecule that propagates the response to most TLRs initiating cascade that ultimately leads to the activation of pro-inflammatory genes by the transcription factor NF-κB [9,10]reported that the expression of MyD88 is upregulated during the intestinal and muscle phases ofT. spiralisinfection.

T. spiraliscan activate and negatively regulate TLRs and interfere with the expression of several genes related to TLRmediated signal transduction pathways to adjust the immune system to its advantage. At intestinal stage ofT. spiralisinfection, the mRNA expression of TLR1, TLR2, TLR3, and TLR4 and TLR9 is up regulated and TLR5 and TLR6 are transiently down regulated. Once the newborn larvae appear, all TLR expression is inhibited, except for TLR2 and only transient upregulationof TLR5 and TLR6 at the encapsulated phase [9,11].

The modulated TLR expression in the small intestine and muscle tissue duringT. spiralisinfection might be closely associated with Treg cell-mediated immune responses and increased cytokine gene expression; IL-10 and TGF-β.[11]TLR2 and TLR4 have been regarded as the main sensors forT. spiralisinfection. An in vitro study showed thatT. spiralisES products suppress dendritic cell maturation by TLR4 [6]. TLR2 and TLR4 are influential by limiting rather than promoting the intestinal immunity; therefore their deficiency accelerated expulsion of theadult worms[12].

In conclusion,T. spiralisinfection can modulate the immune response by regulating the expression of TLRs and their signaling pathways to protect itself from excessive inflammatory responses while maintaining defense against persistent pathogens. Therefore, targeting the central mediators in the inflammatory cascades; TLRs will modulate pathway activation at an earlier point and reduce disease severity. However, further understanding of TLRs and their ligands can lead to novel therapeutic and prophylactic strategies forparasiticinfections [13,14].

References

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